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Brain volumes and cognitive function in MPS IIIB (Sanfilippo syndrome type B): Cross-sectional study
Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130
189 Brain volumes and cognitive function in MPS IIIB (Sanfilippo syndrome type B): Cross-sectional study Igor Nestrasila, Alia Ahmeda, Victor Kovaca, Kyle Rudsera, Katlhleen Delaneya, Ann Barbierb, Chester B. Whitleya, Elsa Shapiroa, aUniversity of Minnesota, Minneapolis, MN, USA, bShire, Lexington, MA, USA
DP
Background: MPS III is predominantly a neurological disease. Quantitative MRI and neurocognitive function may provide understanding of the disease and information about rate of decline. Goals: 1. Collect natural history data and develop outcome measures sensitive to treatment effects; 2. Identification of related changes in cognitive performance. Methods: Cross-sectional quantitative MRI data were collected from children with MPS IIIB during a natural history study (NCT01509768) sponsored by Shire Human Genetic Therapies, Inc. at four centers — the University of Minnesota; Children's Hospital and Research Center, Oakland, CA; Johannes Gutenberg University Medical Center, Mainz, Germany; and the Great Ormond Street Hospital for Children, London, UK. Volumetric analysis was performed by automated segmentation. All volumes were adjusted to intracranial volume. Developmental quotient (DQ) and age equivalent scores were utilized as cognitive outcome. Results: 19 children with MPS IIIB (11 M, 8 F) were enrolled. Mean age was 11.78 years, mean DQ 23.02. DQ declined with age (r2 = 0.42; p b 0.01), mean cortical thickness (r2 = 0.86; p b 0.01E-05) and cortical gray matter loss (r2 = 0.65, p b 0.001). Gray matter loss and mean cortical thickness were significantly related to increasing age (r2 = 0.52, p b 0.01; r2 = 0.42; p b 0.01 respectively). Discussion: Gray matter volume loss with a thinning of cortical mantle is the leading MRI pattern linked to the cognitive decline in MPS IIIB. We demonstrate a quantitative description of disease progression that is a first step to establish an evaluation tool for future therapies.
OF
doi:10.1016/j.ymgme.2014.12.191
Glucocerebrosidase (GC) is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease (GD), a recessive lysosomal disorder, is caused by mutations in the GC gene, GBA1. Gaucher disease has a broad phenotypic spectrum, divided into nonneuropathic and neuropathic forms. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease (PD). There is a lack of appropriate and easy to propagate neuronal models to study the effect of GC in the brain. While patient induced pluripotent stem (iPS) cells, primary rodent neurons, and neuroblastoma cell lines have been used to study the GBA1 and PD link, these models have limitations because of challenges in culturing cells and/or manipulating levels of GC expression. To overcome these difficulties, we established a high yield, easy to culture immortalized mouse neuronal cell model. We immortalized cortical neurons from embryonic null allele gba−/− mice and their control littermates by infecting differentiated primary cortical neurons with an EF1αSV40T lentivirus. After extensive selection with puromycin and FACS-based sorting of CD24 and CD29-positive cells, the immortalized CD24-positive and CD29-positive cells were characterized. Both lines showed no GC enzyme activity or expression of GC protein compared to neurons from WT littermates. The immortalized CD24 neurons were positive for neuronal markers TUJ-1 and MAP-2 but negative for GFAP; the CD29 neurons were positive for GFAP but not for TUJ-1 and MAP-2. Lipidomic analyses revealed significant glycosylsphingosine and glycosylceramide storage in both gba−/− CD24 and CD29 cells. The null allele gba−/− mouse neuronal model, the first neuronal model with total GC deficiency, has proven very useful for the validation of reagents and substrates. Currently, we are immortalizing neuronal cells from our other GD mouse models. These neuronal cell models will provide an easy-to-use tool for the evaluation of novel therapies.
RO
function and visceromegalies, cardiac function, assessment of deformities in joints based on the improvement in mobility and ambulation, as well as levels of glycosaminoglycans (GAG) in urine. Quality of life based on a health questionnaire is evaluated. Clinical improvement was observed after the 10th administration of enzyme replacement therapy with increased physical activity, decreased symptoms in the respiratory tract, and decreased respiratory rudeness, waist circumference and organomegaly. There was no improvement in the joint deformities, however, these were not increased and the patients experienced no pain, thus increasing mobility and a marked improvement in the quality of life of the patients was observed. Early onset of ERT offers improved quality of life for patients with progressive clinical improvement.
S87
TE
doi:10.1016/j.ymgme.2014.12.193
UN
CO
RR
EC
191 When is the best time to start enzyme replacement therapy in patients with cardiac-type Fabry disease? Experience from Taiwan, an area highly prevalent in this cardiac phenotype
doi:10.1016/j.ymgme.2014.12.192
190 Development of a novel neuronal cell model for investigating the link between glucocerebrosidase and Parkinson disease Matthew Nguyena, Wendy Westbroeka, Robert Burnetta, Hideji Fujiwarab, Rohini Sidhub, Bahafta Berhea, Nahid Tayebia, Elma Aflakia, Daniel Oryb, Ellen Sidranskya, aNational Institutes of Health, Bethesda, MD, USA, bWashington University in St. Louis, St. Louis, MO, USA
Dau-Ming Niua,b, Wen-Chung Yua, Ting-Rong Hsua, Fu-Pang Changa, Shih-Hsien Sunga, Tzu-Hung Chua, aTaipei Veteran General Hospital, Taipei, Taiwan, bNational Yang-Ming University Hospital, Taipei, Taiwan
Recent studies revealed that the prevalence of later-onset, cardiac-type Fabry disease is much higher than previously believed. However, the natural course of this disease and the best time to initiate enzyme replacement therapy (ERT) remain poorly understood. In Taiwan, our team first revealed a surprisingly high incidence (approximately 1 in 1600 males and 1 in 800 females) of a cardiac-type GLA mutation, IVS4 + 919G N A (IVS4), in our population. A total of 757 individuals carrying the IVS4 mutation were found at our center. Among these individuals, 96 out of 194 (49%) adult patients (N40 years old) with this mutation had left ventricular hypertrophy, including 51 males (51 out of 66; 77%) and 45 females (45 out of 128; 35%). Endomyocardial biopsy of 30 cardiomyopathic patients with this mutation, who had not previously received ERT, revealed that all patients had significant Gb3 accumulation in their cardiomyocytes. We found that a large proportion of newborns (70% of male and 45% of female newborns) who carried this mutation already had elevated serum globotriaosylsphingosine (lysoGb3) levels during their neonatal period. The lysoGb3 levels increased with patient age, and the rate of disease onset increased with lysoGb3 levels. This finding indicates that the development of hypertrophic cardiomyopathy may follow a long and
189 Brain volumes and cognitive function in MPS IIIB (Sanfilippo syndrome type B): Cross-sectional study Igor Nestrasila, Alia Ahmeda, Victor Kovaca, Kyle Rudsera, Katlhleen Delaneya, Ann Barbierb, Chester B. Whitleya, Elsa Shapiroa, aUniversity of Minnesota, Minneapolis, MN, USA, bShire, Lexington, MA, USA
DP
Background: MPS III is predominantly a neurological disease. Quantitative MRI and neurocognitive function may provide understanding of the disease and information about rate of decline. Goals: 1. Collect natural history data and develop outcome measures sensitive to treatment effects; 2. Identification of related changes in cognitive performance. Methods: Cross-sectional quantitative MRI data were collected from children with MPS IIIB during a natural history study (NCT01509768) sponsored by Shire Human Genetic Therapies, Inc. at four centers — the University of Minnesota; Children's Hospital and Research Center, Oakland, CA; Johannes Gutenberg University Medical Center, Mainz, Germany; and the Great Ormond Street Hospital for Children, London, UK. Volumetric analysis was performed by automated segmentation. All volumes were adjusted to intracranial volume. Developmental quotient (DQ) and age equivalent scores were utilized as cognitive outcome. Results: 19 children with MPS IIIB (11 M, 8 F) were enrolled. Mean age was 11.78 years, mean DQ 23.02. DQ declined with age (r2 = 0.42; p b 0.01), mean cortical thickness (r2 = 0.86; p b 0.01E-05) and cortical gray matter loss (r2 = 0.65, p b 0.001). Gray matter loss and mean cortical thickness were significantly related to increasing age (r2 = 0.52, p b 0.01; r2 = 0.42; p b 0.01 respectively). Discussion: Gray matter volume loss with a thinning of cortical mantle is the leading MRI pattern linked to the cognitive decline in MPS IIIB. We demonstrate a quantitative description of disease progression that is a first step to establish an evaluation tool for future therapies.
OF
doi:10.1016/j.ymgme.2014.12.191
Glucocerebrosidase (GC) is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease (GD), a recessive lysosomal disorder, is caused by mutations in the GC gene, GBA1. Gaucher disease has a broad phenotypic spectrum, divided into nonneuropathic and neuropathic forms. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease (PD). There is a lack of appropriate and easy to propagate neuronal models to study the effect of GC in the brain. While patient induced pluripotent stem (iPS) cells, primary rodent neurons, and neuroblastoma cell lines have been used to study the GBA1 and PD link, these models have limitations because of challenges in culturing cells and/or manipulating levels of GC expression. To overcome these difficulties, we established a high yield, easy to culture immortalized mouse neuronal cell model. We immortalized cortical neurons from embryonic null allele gba−/− mice and their control littermates by infecting differentiated primary cortical neurons with an EF1αSV40T lentivirus. After extensive selection with puromycin and FACS-based sorting of CD24 and CD29-positive cells, the immortalized CD24-positive and CD29-positive cells were characterized. Both lines showed no GC enzyme activity or expression of GC protein compared to neurons from WT littermates. The immortalized CD24 neurons were positive for neuronal markers TUJ-1 and MAP-2 but negative for GFAP; the CD29 neurons were positive for GFAP but not for TUJ-1 and MAP-2. Lipidomic analyses revealed significant glycosylsphingosine and glycosylceramide storage in both gba−/− CD24 and CD29 cells. The null allele gba−/− mouse neuronal model, the first neuronal model with total GC deficiency, has proven very useful for the validation of reagents and substrates. Currently, we are immortalizing neuronal cells from our other GD mouse models. These neuronal cell models will provide an easy-to-use tool for the evaluation of novel therapies.
RO
function and visceromegalies, cardiac function, assessment of deformities in joints based on the improvement in mobility and ambulation, as well as levels of glycosaminoglycans (GAG) in urine. Quality of life based on a health questionnaire is evaluated. Clinical improvement was observed after the 10th administration of enzyme replacement therapy with increased physical activity, decreased symptoms in the respiratory tract, and decreased respiratory rudeness, waist circumference and organomegaly. There was no improvement in the joint deformities, however, these were not increased and the patients experienced no pain, thus increasing mobility and a marked improvement in the quality of life of the patients was observed. Early onset of ERT offers improved quality of life for patients with progressive clinical improvement.
S87
TE
doi:10.1016/j.ymgme.2014.12.193
UN
CO
RR
EC
191 When is the best time to start enzyme replacement therapy in patients with cardiac-type Fabry disease? Experience from Taiwan, an area highly prevalent in this cardiac phenotype
doi:10.1016/j.ymgme.2014.12.192
190 Development of a novel neuronal cell model for investigating the link between glucocerebrosidase and Parkinson disease Matthew Nguyena, Wendy Westbroeka, Robert Burnetta, Hideji Fujiwarab, Rohini Sidhub, Bahafta Berhea, Nahid Tayebia, Elma Aflakia, Daniel Oryb, Ellen Sidranskya, aNational Institutes of Health, Bethesda, MD, USA, bWashington University in St. Louis, St. Louis, MO, USA
Dau-Ming Niua,b, Wen-Chung Yua, Ting-Rong Hsua, Fu-Pang Changa, Shih-Hsien Sunga, Tzu-Hung Chua, aTaipei Veteran General Hospital, Taipei, Taiwan, bNational Yang-Ming University Hospital, Taipei, Taiwan
Recent studies revealed that the prevalence of later-onset, cardiac-type Fabry disease is much higher than previously believed. However, the natural course of this disease and the best time to initiate enzyme replacement therapy (ERT) remain poorly understood. In Taiwan, our team first revealed a surprisingly high incidence (approximately 1 in 1600 males and 1 in 800 females) of a cardiac-type GLA mutation, IVS4 + 919G N A (IVS4), in our population. A total of 757 individuals carrying the IVS4 mutation were found at our center. Among these individuals, 96 out of 194 (49%) adult patients (N40 years old) with this mutation had left ventricular hypertrophy, including 51 males (51 out of 66; 77%) and 45 females (45 out of 128; 35%). Endomyocardial biopsy of 30 cardiomyopathic patients with this mutation, who had not previously received ERT, revealed that all patients had significant Gb3 accumulation in their cardiomyocytes. We found that a large proportion of newborns (70% of male and 45% of female newborns) who carried this mutation already had elevated serum globotriaosylsphingosine (lysoGb3) levels during their neonatal period. The lysoGb3 levels increased with patient age, and the rate of disease onset increased with lysoGb3 levels. This finding indicates that the development of hypertrophic cardiomyopathy may follow a long and